The present invention relates to new derivatives of pyridine having valuable pharmacological properties.
According to the present invention, there are provided compounds of formula: ##STR2## wherein R.sub.1 in the 3- or 5-position of the pyridine nucleus represents a secondary or tertiary carboxamido or carbamyl group when R.sub.2 in the 2-position represents a N-methyl-piperazinyl group as well as the pharmaceutically acceptable acid addition salts of the compounds of formula I.
A process for preparing said compounds of formula I comprises reacting a compound of formula: ##STR3## wherein R.sub.1 in the 3- or 5-position is as defined hereabove and X in the 2-position represents a halogen group with N-methylpyperazine.
The compounds of this invention may be converted, where possible, into their acid addition salts, preferably hydrochlorides, by conventional methods.
In general formula I, R.sub.1 advantageously represents mono- and di-lower alkylcarboxamido, whereas R.sub.2 represents N-methyl-piperazinyl.
The compounds of this invention have interesting anti-inflammatory properties.
The anti-inflammatory properties are determined as follows:
The compounds to be tested are given as freshly prepared solutions or suspensions by oral route one hour before injecting the paw with carrageenan, a known inflammatory agent.
The inflammatory agent either in aqueous solution or suspension is then injected into the plantar tissue of the right hind paw of each rat, the left paw remaining untreated and serving as control. Each animal receives for example 0.05ml of an aqueous solution containing 1 % of carrageenan and 0.9 % of sodium chloride.
4 HOURS AFTER INJECTION, THE IMPORTANCE OF SWELLING IS DETERMINED BY PLETHYSMOGRAPHY AND IS EXPRESSED AS A PERCENT OF THE VOLUME OF THE CONTROL PAW.
The anti-inflammatory effect expressed as a percent of inhibition is obtained by comparison between rats treated with the anti-inflammatory agent and a control group of rats.
The results of the test for anti-inflammatory activity are given in table I.
TABLE I ______________________________________ Acute oedema induced Ref by carrageenan No. Compound of Example % of inhibition ______________________________________ 137 3 51,2 139 5 44,4 141 6 40,0 150 10 32,0 Phenylbutazone 41 Methiazinic acid 46 Acetosalicylic acid 0 Flufenamic acid 34 Niflumic acid 32 ______________________________________ N.B. 100 mg/kg of anti-inflammatory agent are administered by oral route.
According to a further feature of the present invention, we thus provide pharmaceutical compositions comprising as active ingredient, at least one compound according to the present invention, together with a pharmaceutical carrier or excipient. The compositions are generally intended for peroral rectal or parenteral administration and also for external use. Pharmaceutical compositions for oral administration may, for example, be in the form of dosage units such as tablets, dragees or capsules in which at least one of the compounds according to the invention is mixed with a solid pharmaceutical carrier or excipient.
The compositions according to the present invention can also be used in the form of liquid preparations for oral administration especially syrups, elixirs, aqueous dispersions or solutions.
The compositions according to the present invention can also be in the form of solutions for parenteral administration. Solutions or suspensions for injections can be prepared by using, for example, distilled water in which at least one compound employed as active ingredient is dissolved or suspended, if desired, in the presence of a solubilizing agent.
The compositions according to the present invention may also be formulated for rectal administration, for example, the active ingredient in a suppository base.
The anti-inflammatory compositions according to this invention may also be applied for external use, for example, the active ingredient in an ointment base.
The compounds employed as active ingredients in the compositions according to the invention can be administered in varying doses depending on the particular compound being used, the condition of the patient, and the route of administration.
In general, however, the compounds can be administered orally or rectally in doses of from 50 to 1000 mg to be taken one to four times per day, or parenterally in a single dose of 20 to 500 mg per day.